JP5371067B2 - Method for producing high-purity polyethylene glycol aldehyde derivative - Google Patents

Method for producing high-purity polyethylene glycol aldehyde derivative Download PDF

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JP5371067B2
JP5371067B2 JP2011510418A JP2011510418A JP5371067B2 JP 5371067 B2 JP5371067 B2 JP 5371067B2 JP 2011510418 A JP2011510418 A JP 2011510418A JP 2011510418 A JP2011510418 A JP 2011510418A JP 5371067 B2 JP5371067 B2 JP 5371067B2
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ピョンウク パク
ソンニュン キム
ウヒュク チョイ
ハクサン ジャン
ガンサン イ
セチャン ウォン
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Hanmi Science Co Ltd
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Abstract

A method for preparing high-purity polyethyleneglycol-alkylenealdehydes and derivatives thereof is provided.

Description

本発明は、高純度のポリエチレングリコールアルデヒド誘導体（Polyethylene Glycol aldehyde derivatives）を製造する方法に関する。   The present invention relates to a method for producing high-purity polyethylene glycol aldehyde derivatives.

ポリエチレングリコール（Polyethylene Glycol、以下、ＰＥＧ）は、天然高分子、合成高分子とともに水分子と水素結合を效果的にする代表的な親水性高分子として知られている。   Polyethylene glycol (Polyethylene Glycol, hereinafter referred to as PEG) is known as a typical hydrophilic polymer that effectively forms hydrogen bonds with water molecules together with natural and synthetic polymers.

また、多くの有機溶媒に溶ける性質があり、人体毒性がほとんどない物質である。ＰＥＧは、水で完全に伸張された形態の構造を有するため、他の医薬品（蛋白質、ペプチド、酵素、遺伝子等）とコンジュゲイション（conjugation）をさせることによって、立体障害を利用して医薬分子の毒性を減少させ、人体内の免疫システムから医薬分子の活性を保護することができる。従って、人体血漿内の半減期を伸ばす方法で様々な種類の医薬品に応用されることができる。   In addition, it is a substance that is soluble in many organic solvents and has almost no human toxicity. Since PEG has a structure that is completely stretched with water, it can be conjugated with other pharmaceuticals (proteins, peptides, enzymes, genes, etc.) to conjugate pharmaceutical molecules using steric hindrance. The activity of the drug molecule can be protected from the immune system in the human body. Therefore, it can be applied to various kinds of pharmaceuticals by a method of extending the half-life in human plasma.

また、薬効は優れるが、毒性が高く、溶解度が低くて人体に適用し難い医薬品と結合させて、ＰＥＧ-ドラッグ（ＰＥＧ-Ｄｒｕｇ）の溶解度を増加させ、毒性を減少させて、その効能を向上させることができる。   In addition, it has excellent medicinal properties, but is highly toxic and has low solubility, which makes it difficult to apply to the human body to increase the solubility of PEG-drug (PEG-Drug), reduce toxicity, and improve its efficacy Can be made.

ＰＥＧを他の医薬品に導入するためには、ＰＥＧ鎖の末端に多様な官能基を付加して医薬品と結合する方法が主に使われている。   In order to introduce PEG into other pharmaceuticals, a method in which various functional groups are added to the end of the PEG chain and bonded to the pharmaceutical is mainly used.

本発明で言及されるＰＥＧ-プロピオンアルデヒド（PEG-propionaldehyde）も、多様な医薬品と結合して医薬品の溶解度及び効能の増加に使われる物質である。   PEG-propionaldehyde referred to in the present invention is also a substance used in combination with various pharmaceuticals to increase the solubility and efficacy of the pharmaceuticals.

従来、ＰＥＧ-プロピオンアルデヒド（PEG-propionaldehyde）とモトキシポリエチレングリコール-プロピオンアルデヒド（Methoxy PEG-propionaldehyde、以下、mPEG-propionaldehyde）は、ポリエチレングリコール末端のヒドロキシ基を酸化させたり、或いは、アセタール基を導入後、加水分解反応のような方法で得ることができる。例えば、ＵＳ６，４６５，６９４号ではＰＥＧ-アルデヒド誘導体を製造する方法として、ＰＥＧ及び触媒混合物に酸素気体を加えて−ＣＨ２ＯＨ基を−ＣＨＯに酸化する方法を開示している。然しながら、大部分の酸化反応条件は、ＰＥＧ鎖を分解させる結果を招くことがありでき、末端にアセタール基を導入する反応は、反応時に使われる大部分の原料が高価であるため、商業化が難しいといえる。 Conventionally, PEG-propionaldehyde and PEG-propionaldehyde (Methoxy PEG-propionaldehyde, hereinafter referred to as mPEG-propionaldehyde) oxidize the hydroxy group at the end of polyethylene glycol or introduce an acetal group. Thereafter, it can be obtained by a method such as a hydrolysis reaction. For example, US Pat. No. 6,465,694 discloses a method for producing a PEG-aldehyde derivative by adding oxygen gas to PEG and a catalyst mixture to oxidize —CH 2 OH groups to —CHO. However, most oxidation reaction conditions can result in the degradation of the PEG chain, and the reaction of introducing an acetal group at the end is expensive because most of the raw materials used during the reaction are expensive. It's difficult.

一方、ＰＥＧを薬物につける技術（PEGylation）に関連付けられた従来技術として、ＵＳ４，００２，５３１（Pierce Chemical Company）ではｍＰＥＧ（１Ｋ）をＭｎＯ２で酸化させて、ｍ-ＰＥＧアセトアルデヒド（mPEG Acetaldehyde）を製造した後、トリプシン酵素（Enzyme Trypsin）に結合させて（pegylation）薬物伝達システム（Drug Delivery System）として使用した。このような酸化反応は、ＰＥＧ鎖の分解現象による分布度の増加現象が観察されることができ、反応転換率も８０％以下に現れる現象を示す。 On the other hand, US Pat. No. 4,002,531 (Pierce Chemical Company) as a conventional technique related to a technique for attaching PEG to a drug (PEGylation) oxidizes mPEG (1K) with MnO 2 to produce m-PEG acetaldehyde (mPEG Acetaldehyde). Was then used as a drug delivery system by pegylation with trypsin enzyme (Enzyme Trypsin). In such an oxidation reaction, an increase in the degree of distribution due to the decomposition phenomenon of the PEG chain can be observed, and the reaction conversion rate also appears at 80% or less.

Ｊ．Ｐｏｌｙｍ．Ｓｃｉ．Ｅｄ、１９８４、２２、ｐｐ３４１〜３５２ではＰＥＧ（３．４Ｋ）をブロモアセトアルデヒド（bromoacetaldehyde）と反応してＰＥＧ-ａｃｅｔａｌを製造した後、加水分解してＰＥＧアセトアルデヒド（PEG-acetaldehyde）を製造した。論文で提示された末端基のアルデヒド活性化程度は６５％であり、残りの３５％程度は未反応ヒドロキシ基として残存していると言える。精製過程をたどらない状態で薬物伝達システムに使用するのは難しいといえる。 J. et al. Polym. Sci. In Ed, 1984, 22, and pp 341-352, PEG (3.4K) was reacted with bromoacetaldehyde to produce PEG-acetal, followed by hydrolysis to produce PEG-acetaldehyde. It can be said that the aldehyde activation degree of the terminal group presented in the paper is 65%, and the remaining 35% remains as an unreacted hydroxy group. It is be said difficult to use in a drug delivery system without follow the purification process.

ＵＳ４，００２，５３１（The University of Alabama in Huntsville）ではアセタール基を有する低分子とＰＥＧを反応する時、ＰＥＧ鎖の末端のヒドロキシ基を反応性が優れるチオール（-ＳＨ）基に置換して反応を進行した。一般的なＰＥＧ−ＯＨは、反応性が低いため、単分子と求核置換反応をし難いため、活性化程度もＪ．Ｐｏｌｙｍ．Ｓｃｉ．Ｅｄ、１９８４、２２、ｐｐ３４１〜３５２で例示した水準（約６５％）から大きく外れないと予想される。   In US 4,002,531 (The University of Alabama in Huntsville), when reacting a small molecule having an acetal group with PEG, the hydroxyl group at the end of the PEG chain is replaced with a thiol (-SH) group having excellent reactivity. Proceeded. Since general PEG-OH has low reactivity, it is difficult to perform a nucleophilic substitution reaction with a single molecule. Polym. Sci. Ed, 1984, 22, and pp 341 to 352 are expected to not greatly deviate from the level (about 65%).

ＵＳ５，９９０，２３７（Shearwater Polymers,Inc）では多様な水溶性高分子の末端にアルデヒド基を導入してアミングループを有する多様な活性物質（proteins, enzymes、Polypeptides, drugs、dyes、nucleosides, oligonucleotides、lipids, phospholipids, liposomes等）と反応して高分子鎖内にエステル基のように加水分解が容易に進行されるグループ無しに水溶液上で安定した高分子を製造する方法を例示した。例示した反応でアルデヒドの純度は８５〜９８％程度であり、反応に応じて相当な差を示している。   US 5,990,237 (Shearwater Polymers, Inc.) introduces an aldehyde group at the end of various water-soluble polymers and has various active substances (proteins, enzymes, Polypeptides, drugs, dyes, nucleosides, oligonucleotides, Lipids, phospholipids, phospholipids, etc.) and a method for producing a stable polymer on an aqueous solution without a group in which hydrolysis proceeds easily like an ester group in the polymer chain was exemplified. In the exemplified reaction, the purity of the aldehyde is about 85 to 98%, indicating a considerable difference depending on the reaction.

ＷＯ２００４／０１３２０５ Ａ１（Ｆ．ＨＯＦＦＭＡＮＮ-ＬＡ ＲＯＣＨＥ ＡＧ）、ＵＳ６，９５６，１３５ Ｂ２（Ｓｕｎ Ｂｉｏ，Ｉｎｃ）ではＰＥＧ末端にアルデヒド基を有するが、ＰＥＧ鎖内にカルボニル基や窒素が含まれている物質を製造した。これは酸素と水素のみでなっているＰＥＧ鎖の物性とは異なる物性を示す可能性があり、段階別精製過程無しにＰＥＧの末端の官能基を変化するため、副産物（未反応ＰＥＧ）の生成可能性が高いといえる。   In WO2004 / 013205 A1 (F. HOFFMANN-LA ROCHE AG), US 6,956,135 B2 (Sun Bio, Inc), a substance having an aldehyde group at the PEG end but containing a carbonyl group or nitrogen in the PEG chain Manufactured. This may be different from the physical properties of PEG chains consisting only of oxygen and hydrogen, and the functional group at the end of PEG is changed without a step-by-step purification process, resulting in the formation of by-products (unreacted PEG). It is highly possible.

本発明の目的は、ＰＥＧ鎖の分解なしに、ＰＥＧまたはＰＥＧ末端のアルコール基のうち一つがアルコキシに置換されたＰＥＧ誘導体（以下、アルコキシ-ＰＥＧ）のヒドロキシ基をアルデヒド基に転換することができる製造方法を提供することである。   The object of the present invention is to convert the hydroxy group of a PEG derivative (hereinafter referred to as alkoxy-PEG) in which one of the PEG or PEG terminal alcohol groups is substituted with alkoxy without decomposition of the PEG chain to an aldehyde group. It is to provide a manufacturing method.

より具体的に、多様な医薬品と結合して医薬品の溶解度及び効能の増加に使われる物質であるＰＥＧまたはｍＰＥＧなどのアルコキシ-ＰＥＧからＰＥＧアルデヒドまたはアルコキシ-ＰＥＧアルデヒドを不純物無しに経済的に製造することができる製造方法を提供することである。   More specifically, PEG aldehyde or alkoxy-PEG aldehyde is economically produced without impurities from alkoxy-PEG, such as PEG or mPEG, which is used to increase the solubility and efficacy of pharmaceuticals by combining with various pharmaceuticals. It is to provide a manufacturing method that can.

前述した本発明の目的を達成するために努力した結果、本発明者は、ポリエチレングリコール（Polyethylene glycol、以下、ＰＥＧ）またはアルコキシポリエチレングリコール（alkoxy polyethyleneglycol、以下、アルコキシ-ＰＥＧ）をマイルドな条件（Pfitzner-Moffat oxidation）で酸化反応させて末端のヒドロキシ基をアルデヒド基に転換したり、或いはＰＥＧまたはアルコキシ-ＰＥＧ末端にヒドロキシ（Ｃ３〜Ｃ１０）アルキル基を導入した後、マイルドな条件（Pfitzner-Moffat oxidation）で酸化反応させて末端のヒドロキシ基をアルデヒド基に転換する方法を使用することによって、ＰＥＧ鎖の分解による低分子量のＰＥＧ生成を最小化することができることを見出した。   As a result of striving to achieve the above-described object of the present invention, the present inventor has found that polyethylene glycol (hereinafter referred to as PEG) or alkoxy polyethylene glycol (hereinafter referred to as alkoxy-PEG) is treated under mild conditions (Pfitzner). -Moffat oxidation) to convert the terminal hydroxy group to an aldehyde group, or after introducing a hydroxy (C3-C10) alkyl group to the PEG or alkoxy-PEG end, mild conditions (Pfitzner-Moffat oxidation) It was found that the production of low molecular weight PEG due to degradation of the PEG chain can be minimized by using the method of converting the terminal hydroxy group to an aldehyde group by oxidation reaction in (1).

本発明に係る製造方法は、巨大高分子の末端のアルコール基をＰＥＧ鎖の分解無しに定量的にアルデヒド基に転換することができ、使われる大部分の物質が商業的に使用可能な物質であり、反応も特殊な製造施設（低温、高温、高圧等）を必要としないため、経済的な方法により商業的生産が可能な方法といえる。   The production method according to the present invention can quantitatively convert the alcohol group at the end of a macromolecule to an aldehyde group without decomposition of the PEG chain, and most of the substances used are commercially usable substances. In addition, since the reaction does not require special manufacturing facilities (low temperature, high temperature, high pressure, etc.), it can be said that commercial production is possible by an economical method.

本発明の第１の態様によるＰＥＧアルデヒド誘導体の製造方法は、下記式２のＰＥＧ誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させて、下記式１のＰＥＧアルデヒドを製造する方法である。
［式中、ｎは３〜２０００の整数、ｍは２〜１０の整数である。］ The method for producing a PEG aldehyde derivative according to the first aspect of the present invention is a method for producing a PEG aldehyde of the following formula 1 by reacting a PEG derivative of the following formula 2 with dimethyl sulfoxide and dicyclohexylcarbodiimide.
[Wherein, n is an integer of 3 to 2000, and m is an integer of 2 to 10. ]

本発明に係る第２の態様によるＰＥＧアルデヒド誘導体の製造方法は、下記式１１のＰＥＧ誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させて、下記式１０のＰＥＧアルデヒドを製造する方法である。
［式中、ｎは３〜２０００の整数、ｍは２〜１０の整数、Ｒ２は（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ The method for producing a PEG aldehyde derivative according to the second aspect of the present invention is a method for producing a PEG aldehyde of the following formula 10 by reacting a PEG derivative of the following formula 11 with dimethyl sulfoxide and dicyclohexylcarbodiimide.
[Wherein, n is an integer of 3 to 2000, m is an integer of 2 to 10, R 2 is selected from (C1 to C7) alkyl, or (C6 to C20) ar (C1 to C7) alkyl group. ]

以下、本発明をより詳細に説明する。   Hereinafter, the present invention will be described in more detail.

このとき、使われる技術用語及び科学用語において他の正義がない場合、この発明が属する技術分野において、通常の知識を有する者が通常的に理解している意味を有する。また、従来と同様な技術的構成及び作用に対する重複の説明は省略する。   At this time, if there is no other justice in the technical terms and scientific terms used, it has the meaning normally understood by those having ordinary knowledge in the technical field to which this invention belongs. In addition, the redundant description of the technical configuration and operation similar to the conventional one is omitted.

本発明の第１の態様によるＰＥＧアルデヒド製造方法は、下記式２のＰＥＧ誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させることによって、ＰＥＧ鎖が分解されずに下記式２のアルコール基をアルデヒドに酸化させることができ、式１のＰＥＧアルデヒドをＰＥＧ鎖の分解物である低分子量ＰＥＧまたはＰＥＧ酸などの不純物含有量が低い高純度物質で製造することができる。
［式中、ｎは３〜２０００の整数、ｍは２〜１０の整数である。］ In the method for producing PEG aldehyde according to the first aspect of the present invention, a PEG derivative of the following formula 2 is reacted with dimethyl sulfoxide and dicyclohexylcarbodiimide to oxidize an alcohol group of the following formula 2 to an aldehyde without decomposing the PEG chain. The PEG aldehyde of Formula 1 can be prepared with a high purity material having a low impurity content such as low molecular weight PEG or PEG acid which is a degradation product of PEG chain.
[Wherein, n is an integer of 3 to 2000, and m is an integer of 2 to 10. ]

前記反応は、より具体的に、前記式２のＰＥＧ誘導体にジメチルスルホキシド、トリフルオロ酢酸及びピリジンを加えて混合した後、ジシクロヘキシルカルボジイミドを入れて反応させることであり、前記反応後、ヘプタン及びイソプロピルアルコール混合溶媒の下に結晶化した後、アセトニトリル（Acetonitrile、以下、ＡＮ）及びメチルｔ-ブチルエーテル（Methyl t-Butyl Ether、以下、ＭＴＢＥ）混合液で再結晶する過程をさらに含むことができる。 The reaction is more specifically, the formula 2 of the PEG derivative in dimethyl sulfoxide, was mixed with trifluoroacetic acid and pyridine, is to react put dicyclohexylcarbodiimide, after the reaction, heptane and isopropyl pin The method may further include a step of crystallization in a mixed solvent of alcohol and then recrystallizing with a mixed liquid of acetonitrile (hereinafter referred to as AN) and methyl t-butyl ether (hereinafter referred to as MTBE).

本発明の第１の態様によるＰＥＧアルデヒド製造方法のうち、ＰＥＧ末端にＣ３〜Ｃ１０のアルデヒド基を有するＰＥＧアルデヒドの製造方法は、具体的に、下記式３のＰＥＧ末端にヒドロキシ（Ｃ３〜Ｃ１０）アルキル基を導入して下記式４のＰＥＧ誘導体を製造する段階、及び前記式４の誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させる酸化反応を介して前記式１のＰＥＧアルデヒドを製造する段階、を含む。
［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数である。］ Among the methods for producing PEG aldehyde according to the first aspect of the present invention, the method for producing PEG aldehyde having a C3 to C10 aldehyde group at the PEG end is specifically hydroxy (C3 to C10) at the PEG end of the following formula 3. Introducing an alkyl group to produce a PEG derivative of formula 4 below, and producing an PEG aldehyde of formula 1 via an oxidation reaction in which the derivative of formula 4 is reacted with dimethyl sulfoxide and dicyclohexylcarbodiimide. .
[Wherein, n is an integer of 3 to 2000, and k is an integer of 3 to 10. ]

前記式４のＰＥＧ誘導体を製造する方法は、具体的に、下記の段階を含んで行われる。
ａ）下記式３のＰＥＧと下記式５のシアノアルケン（cyano alkene）を反応させて、下記式６のシアノアルキル-ＰＥＧを製造する段階；
ｂ）下記式６のシアノアルキル-ＰＥＧから式７のＰＥＧ-カルボン酸を製造する段階；
ｃ）下記式７のＰＥＧ-カルボン酸を下記式８のアルコールと反応させて、下記式９のＰＥＧ-エステル化合物を製造する段階；及び、
ｄ）下記式９のＰＥＧ-エステル化合物を還元させて、下記式４のＰＥＧ誘導体を製造する段階。
［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数、Ｒ１は（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ Specifically, the method for preparing the PEG derivative of Formula 4 includes the following steps.
a) reacting a PEG of formula 3 below with a cyano alkene of formula 5 below to produce a cyanoalkyl-PEG of formula 6 below;
b) preparing a PEG-carboxylic acid of formula 7 from a cyanoalkyl-PEG of formula 6 below;
c) reacting a PEG-carboxylic acid of formula 7 below with an alcohol of formula 8 below to produce a PEG-ester compound of formula 9 below; and
d) reducing a PEG-ester compound of formula 9 below to produce a PEG derivative of formula 4 below.
[Wherein, n is an integer of 3 to 2000, k is an integer of 3 to 10, and R 1 is selected from (C1-C7) alkyl or (C6-C20) ar (C1-C7) alkyl groups. ]

前記式４のＰＥＧ誘導体を製造するための段階のうち、前記ｂ）段階及びｄ）段階のうちいずれか一つ以上の段階後、反応副産物、特にＰＥＧ及びＰＥＧ酸（acid）をイオン交換樹脂カラムを用いて分離することによって、生成物を精製する過程をさらに含むことが好ましい。   Among the steps for preparing the PEG derivative of Formula 4, after any one or more of the steps b) and d), reaction by-products, particularly PEG and PEG acid are converted into an ion exchange resin column. Preferably, the method further comprises the step of purifying the product by separation using

また、本発明の第２の態様によるＰＥＧアルデヒド製造方法は、下記式１１のＰＥＧ誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させることによって、ＰＥＧ鎖が分解されずに下記式１１のアルコール基をアルデヒドに酸化させることができ、式１０のＰＥＧアルデヒドをＰＥＧ鎖の分解物である低分子量ＰＥＧまたはＰＥＧ酸などの不純物含有量が低い高純度物質で製造することができる。
［式中、ｎは３〜２０００の整数、ｍは２〜１０の整数、Ｒ２は（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ Further, in the method for producing PEG aldehyde according to the second aspect of the present invention, by reacting a PEG derivative of the following formula 11 with dimethyl sulfoxide and dicyclohexylcarbodiimide, the alcohol group of the following formula 11 is converted into an aldehyde without decomposition of the PEG chain. The PEG aldehyde of formula 10 can be made with a high purity material with a low impurity content such as low molecular weight PEG or PEG acid, which is a degradation product of the PEG chain.
[Wherein, n is an integer of 3 to 2000, m is an integer of 2 to 10, R 2 is selected from (C1 to C7) alkyl, or (C6 to C20) ar (C1 to C7) alkyl group. ]

前記式１１で、Ｒ２は、より具体的に、メチル、エチル、プロピル、ブチル、ベンジルを例示することができる。 In Formula 11, R 2 can be more specifically exemplified by methyl, ethyl, propyl, butyl and benzyl.

前記反応は、より具体的には、前記式１１のＰＥＧ誘導体にジメチルスルホキシド、トリフルオロ酢酸及びピリジンを加えて混合した後、ジシクロヘキシルカルボジイミドを入れて反応させることであり、前記反応後、ヘプタン及びイソプロピルアルコール混合溶媒の下に結晶化した後、ＡＮ／ＭＴＢＥ混合液で再結晶する過程をさらに含むことができる。 More specifically, the reaction is to add dimethyl sulfoxide, trifluoroacetic acid and pyridine to the PEG derivative of the formula 11 and mix, and then add dicyclohexylcarbodiimide to react. After the reaction, heptane and isopropyl after crystallization under Pi alcohol mixed solvent may further include the step of recrystallization aN / MTBE mixture.

本発明の第２の態様によるＰＥＧアルデヒド製造方法のうち、ＰＥＧ末端にＣ３〜Ｃ１０のアルデヒド基を有するＰＥＧアルデヒドの製造方法は、具体的に、下記式１２のアルコキシ-ＰＥＧ末端にヒドロキシ（Ｃ３〜Ｃ１０）アルキル基を導入して前記式１３のアルコキシ-ＰＥＧ誘導体を製造する段階、及び前記式１３の誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させる酸化反応を介して前記式１０のＰＥＧアルデヒドを製造する段階、を含む。
［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数、Ｒ２は（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ Among the methods for producing PEG aldehyde according to the second aspect of the present invention, the method for producing PEG aldehyde having a C3-C10 aldehyde group at the PEG end is specifically a hydroxy (C3- C10) Producing the alkoxy-PEG derivative of formula 13 by introducing an alkyl group, and producing the PEG aldehyde of formula 10 through an oxidation reaction in which the derivative of formula 13 is reacted with dimethyl sulfoxide and dicyclohexylcarbodiimide. Stages.
[Wherein, n is an integer of 3 to 2000, k is an integer of 3 to 10, and R 2 is selected from (C1-C7) alkyl or (C6-C20) ar (C1-C7) alkyl groups. ]

前記式１２及び式１３で、Ｒ２は、より具体的に、メチル、エチル、プロピル、ブチル、ベンジルを例示することができる。 In Formula 12 and Formula 13, R 2 can be more specifically exemplified by methyl, ethyl, propyl, butyl, and benzyl.

前記式１３のアルコキシ-ＰＥＧ誘導体を製造する方法は、具体的に、下記の段階を含んで行われる。
ａ）下記式１２のアルコキシ-ＰＥＧと下記式５のシアノアルケン（cyano alkene）を反応させて、下記式１４のアルコキシ-ＰＥＧニトリル化合物を製造する段階；
ｂ）下記式１４のアルコキシ-ＰＥＧニトリル化合物から式１５のアルコキシ-ＰＥＧカルボン酸を製造する段階；
ｃ）下記式１５のアルコキシ-ＰＥＧカルボン酸を下記式８のアルコールと反応させて、下記式１６のアルコキシ-ＰＥＧエステル化合物を製造する段階；及び、
ｄ）下記式１６のアルコキシ-ＰＥＧエステル化合物を還元させて、下記式１３のＰＥＧ誘導体を製造する段階。
［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数、Ｒ１及びＲ２は独立的に（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ The method for preparing the alkoxy-PEG derivative of formula 13 is specifically performed including the following steps.
a) reacting an alkoxy-PEG of the following formula 12 with a cyano alkene of the following formula 5 to produce an alkoxy-PEG nitrile compound of the following formula 14;
b) preparing an alkoxy-PEG carboxylic acid of formula 15 from an alkoxy-PEG nitrile compound of formula 14 below;
c) reacting an alkoxy-PEG carboxylic acid of formula 15 below with an alcohol of formula 8 below to produce an alkoxy-PEG ester compound of formula 16 below; and
d) A step of reducing an alkoxy-PEG ester compound of the following formula 16 to produce a PEG derivative of the following formula 13.
[Wherein, n is an integer of 3 to 2000, k is an integer of 3 to 10, R 1 and R 2 are independently (C1-C7) alkyl, or (C6-C20) ar (C1-C7) alkyl group. Selected from. ]

前記式５、式８、及び式１２ないし式１６で、Ｒ１及びＲ２は、より具体的に、メチル、エチル、プロピル、ブチル、ベンジルを例示することができる。 In Formula 5, Formula 8, and Formulas 12 to 16, R 1 and R 2 may be more specifically exemplified by methyl, ethyl, propyl, butyl, and benzyl.

前記式１３のＰＥＧ誘導体を製造するための段階のうち、前記ｂ）段階及びｄ）段階のうちいずれか一つ以上の段階後、反応副産物、特にＰＥＧ及びＰＥＧ酸（acid）をイオン交換樹脂カラムを用いて分離することによって、生成物を精製する過程をさらに含むことが好ましい。   Among the steps for preparing the PEG derivative of Formula 13, after any one or more of the steps b) and d), reaction by-products, particularly PEG and PEG acid are converted into an ion exchange resin column. Preferably, the method further comprises the step of purifying the product by separation using

本発明ではＰＥＧまたはアルコキシ-ＰＥＧからシアン化（Cyanation）、加水分解（Hydrolysis）、エステル化（Esterification）、還元（Reduction）、酸化（Oxidation）反応を進行してＰＥＧアルデヒド（PEGaldehyde）またはアルコキシ-ＰＥＧアルデヒドを製造した。各加水分解と還元過程で生成される副産物、特にＰＥＧ及びＰＥＧ酸（acid）は、イオン交換樹脂カラムを用いて分離、精製する場合、次の反応における副産物の生成を最小化させることができ、巨大高分子の末端のアルコール基をＰＥＧ鎖の分解なしに定量的にアルデヒド基に転換することができる。また、本発明に係る製造方法に使われる物質は、商業的に使用可能であり、反応も特殊な製造施設（低温、高温、高圧等）を必要としないため、経済的な方法により商業的生産が可能な方法であるといえる。   In the present invention, PEG or alkoxy-PEG proceeds from PEG or alkoxy-PEG through cyanation, hydrolysis, esterification, reduction, oxidation, and oxidation reactions. An aldehyde was produced. By-products generated during each hydrolysis and reduction process, especially PEG and PEG acid, when separated and purified using an ion exchange resin column, the generation of by-products in the next reaction can be minimized, The terminal alcohol group of the macromolecule can be quantitatively converted to an aldehyde group without degradation of the PEG chain. In addition, since the materials used in the production method according to the present invention can be used commercially, and the reaction does not require special production facilities (low temperature, high temperature, high pressure, etc.), commercial production is achieved by an economical method. Can be said to be a possible method.

以下、実施例を介して本発明をさらに具体的に説明するが、本発明が下記の実施例に限定されることではない。また、％は別途に言及しない場合、モル％を意味する。   Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples. Further,% means mol% unless otherwise mentioned.

［実施例１］ＰＥＧ-プロピオンアルデヒドの製造 [Example 1] Production of PEG-propionaldehyde

[化学式１]
[Chemical formula 1]

前記反応式に示した通り、ＰＥＧ-プロピオンアルデヒドを製造し、製造段階別具体的な製造方法は、次の通りである。   As shown in the reaction formula, PEG-propionaldehyde is produced, and a specific production method according to the production steps is as follows.

＜シアン化＞ <Cyanation>

反応器にＰＥＧ（数平均分子量３．４Ｋ）１００ｇを蒸留水６００ｍｌに溶解し、ＫＯＨ４５ｇを入れた後、１〜５℃に冷却する。冷却後、アクリロニトリル（Ａｃｒｙｌｏｎｉｔｒｉｌｅ）１６ｇを入れた後、３日間反応させる。反応終了後、ＭＣ４００ｍｌで３回抽出して溶媒を完全に除去する。   In a reactor, 100 g of PEG (number average molecular weight 3.4 K) is dissolved in 600 ml of distilled water, 45 g of KOH is added, and then cooled to 1 to 5 ° C. After cooling, 16 g of acrylonitrile is added, followed by reaction for 3 days. After completion of the reaction, the solvent is completely removed by extracting 3 times with 400 ml of MC.

収率：１１０ｇ
１Ｈ-ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ３）：ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ２ＣＨ２ＣＮ（ｔ，２．６３ｐｐｍ） Yield: 110g
1 H-NMR (200 MHz, CDCl 3 ): PEG backbone (m, 3.20 to 4.20 ppm), —OCH 2 CH 2 CN (t, 2.63 ppm)

＜加水分解及び精製＞ <Hydrolysis and purification>

濃縮残留物（Residue）１１０ｇにｃ−ＨＣｌ５００ｍｌを入れた後、常温で２日間反応させる。ＭＣ４００ｍｌで３回抽出した後、ＭＣを完全に濃縮する。濃縮残留物（Residue）９５ｇに１０％ＫＯＨ溶液６００ｍｌ入れた後、常温で２日間反応する。反応終了後、ＭＣ３００ｍｌで３回抽出して溶媒層を濃縮する。エチルエーテル１．２Ｌを入れて０℃で結晶化、ろ過、乾燥して白色粉末８８ｇを収得した。乾燥された白色粉末状固体をイオン交換樹脂カラムを用いて精製する。   After adding 500 ml of c-HCl to 110 g of concentrated residue (Residue), the mixture is reacted at room temperature for 2 days. After extracting 3 times with 400 ml of MC, MC is concentrated completely. After adding 600 ml of a 10% KOH solution to 95 g of the concentrated residue (Residue), the mixture is reacted at room temperature for 2 days. After completion of the reaction, the solvent layer is concentrated by extracting 3 times with 300 ml of MC. 1.2 L of ethyl ether was added, crystallized at 0 ° C., filtered and dried to obtain 88 g of white powder. The dried white powdery solid is purified using an ion exchange resin column.

収率：５２ｇ（ＨＰＬＣ ｐｕｒｉｔｙ：９９．９４％）
１Ｈ-ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ３）：ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ２ＣＨ２Ｃ（Ｏ）ＯＨ（ｔ，２．６０ｐｐｍ） Yield: 52 g (HPLC purity: 99.94%)
1 H-NMR (200 MHz, CDCl 3 ): PEG backbone (m, 3.20 to 4.20 ppm), —OCH 2 CH 2 C (O) OH (t, 2.60 ppm)

＜エステル化反応＞ <Esterification reaction>

精製されたＰＥＧ酸（PEG diacid）５２ｇをＭｅＯＨ４００ｍｌ、Ｈ２ＳＯ４２．２５ｇを入れて常温で２日間反応を進行した後、ＭＣ３００ｍｌで３回抽出を進行する。溶媒層を完全に濃縮する。 After adding 52 g of purified PEG acid (PEG diacid) 400 ml of MeOH and 2.25 g of H 2 SO 4, the reaction proceeds at room temperature for 2 days, and then extraction is performed 3 times with 300 ml of MC. Concentrate the solvent layer completely.

収率：５１ｇ
１Ｈ-ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ３）：ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ３（ｓ，３．５０ｐｐｍ）−ＯＣＨ２ＣＨ２Ｃ（Ｏ）ＯＣＨ３（ｔ，２．６０ｐｐｍ） Yield: 51g
1 H-NMR (200 MHz, CDCl 3 ): PEG backbone (m, 3.20 to 4.20 ppm), —OCH 3 (s, 3.50 ppm) —OCH 2 CH 2 C (O) OCH 3 (t, 2 .60 ppm)

＜還元及び精製＞ <Reduction and purification>

濃縮残留物（Residue）５１ｇにＭＣ３０ｍｌ、ＭｅＯＨ３０ｍｌを入れて３０分間撹拌後、ＮａＢＨ４３ｇを入れて２４時間反応させる。反応終了後、大部分の溶媒を除去し、１Ｎ-ＮａＯＨ溶液４００ｍｌを入れた後、内部８０℃で１時間撹拌する。冷却後、ｃｏｎｃ-ＨＣｌでｐＨ１．５〜２に調節し、ＭＣ２００ｍｌで３回抽出する。ＭＴＢＥ（methyl tert-butyl ether）６００ｍｌで結晶化、ろ過、乾燥して白色粉末４２ｇを得た。乾燥された白色粉末状固体をイオン交換樹脂カラムを用いて精製する。 To 51 g of the concentrated residue (Residue), 30 ml of MC and 30 ml of MeOH are added and stirred for 30 minutes, and then 3 g of NaBH 4 is added and reacted for 24 hours. After completion of the reaction, most of the solvent is removed and 400 ml of 1N-NaOH solution is added, followed by stirring at 80 ° C. for 1 hour. After cooling, adjust to pH 1.5-2 with conc-HCl and extract 3 times with 200 ml of MC. Crystallization with 600 ml of MTBE (methyl tert-butyl ether), filtration and drying gave 42 g of white powder. The dried white powdery solid is purified using an ion exchange resin column.

収率：３０ｇ（ＨＰＬＣ ｐｕｒｉｔｙ：１００％）
ＧＰＣ：Ｍｎ（３０２３）、ＰＤＩ（Ｐｏｌｙｄｉｓｐｅｒｓｉｔｙ）＝１．０２
１Ｈ-ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ３）：ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ２ＣＨ２ＣＨ２ＯＨ（ｔ，２．６２ｐｐｍ）、−ＯＣＨ２ＣＨ２ＣＨ２ＯＨ（ｔ，１．８３ｐｐｍ） Yield: 30 g (HPLC purity: 100%)
GPC: Mn (3023), PDI (Polydispersity) = 1.02
1 H-NMR (200 MHz, CDCl 3 ): PEG backbone (m, 3.20 to 4.20 ppm), —OCH 2 CH 2 CH 2 OH (t, 2.62 ppm), —OCH 2 CH 2 CH 2 OH ( t, 1.83 ppm)

＜酸化＞ <Oxidation>

ＰＥＧプロピルアルコール（PEG propyl alcohol）４２ｇをＭＣ８０ｍｌに溶解し、ＤＭＳＯ９４ｍｌを入れた後、内部温度を０〜５℃に冷却する。ピリジン（Pyridine）３ｇ、ＴＦＡ（Trifluoroacetic acid）４ｇを入れた後、同一温度で１ｈｒ撹拌する。ＤＣＣ（Dicyclohexylcarbodimide）１０ｇを入れた後、常温で２４時間反応させる。反応終了後、ろ過して析出されたＤＣＵ（Dicyclohexylurea）を除去する。ろ過後、予め用意したヘプタン／イソプロピルアルコール（Ｈｅｐｔａｎｅ／ＩＰＡ）（７：３Ｖｏｌ％）１０８８ｍｌを入れて、冷却、結晶化し、収得された固体物質をＡＮ／ＭＴＢＥ（５：１）溶液を用いて再結晶した後に乾燥する。 After dissolving 42 g of PEG propyl alcohol in 80 ml of MC and adding 94 ml of DMSO, the internal temperature is cooled to 0-5 ° C. After adding 3 g of pyridine (Pyridine) and 4 g of TFA (Trifluoroacetic acid), the mixture is stirred at the same temperature for 1 hr. After adding DCC (Dicyclohexylcarbodimide) 10g, it is made to react at normal temperature for 24 hours. After completion of the reaction, DCU (Dicyclohexylurea) deposited by filtration is removed. After filtration, previously prepared heptane / isopropyl Pi alcohol (Heptane / IPA): Put (7 3Vol%) 1088ml, cooled, crystallized, Shutoku solid material AN / MTBE (5: 1) solution using a And recrystallized to dry.

収率：２５ｇ（ｂｙ ＮＭＲ ｐｕｒｉｔｙ：９９．７３％）
ＧＰＣ（ｍＰＥＧ）：Ｍｎ（３１５６）、ＰＤＩ（Ｐｏｌｙｄｉｓｐｅｒｓｉｔｙ）＝１．０２
ＧＰＣ：Ｍｎ（３０１０）、ＰＤＩ（Polydispersity）＝１．０２
１Ｈ-ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）：−Ｃ（Ｏ）Ｈ（ｓ，９．８０ｐｐｍ）、ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ２ＣＨ２Ｃ（Ｏ）Ｈ（ｔ，２．６０ｐｐｍ） Yield: 25 g (by NMR purity: 99.73%)
GPC (mPEG): Mn (3156), PDI (Polydispersity) = 1.02
GPC: Mn (3010), PDI (Polydispersity) = 1.02
1 H-NMR (500 MHz, CDCl 3 ): —C (O) H (s, 9.80 ppm), PEG backbone (m, 3.20 to 4.20 ppm), —OCH 2 CH 2 C (O) H ( t, 2.60 ppm)

［実施例２］ｍＰＥＧ-プロピオンアルデヒドの製造 [Example 2] Production of mPEG-propionaldehyde

実施例１と同様の方法により、ｍＰＥＧ（数平均分子量２０Ｋ）からｍＰＥＧ（数平均分子量２０Ｋ）-プロピオンアルデヒド（mPEG-propion aldehyde）を製造した。   In the same manner as in Example 1, mPEG (number average molecular weight 20K) -propionaldehyde (mPEG-propion aldehyde) was produced from mPEG (number average molecular weight 20K).

収率：６０％（ｆｒｏｍ ｍＰＥＧ、ｂｙ ＮＭＲ ｐｕｒｉｔｙ：９９．７３％）
１Ｈ-ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）：−Ｃ（Ｏ）Ｈ（ｓ，９．８０ｐｐｍ）、ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ２ＣＨ２Ｃ（Ｏ）Ｈ（ｔ，２．６０ｐｐｍ） Yield: 60% (from mPEG, by NMR purity: 99.73%)
1 H-NMR (500 MHz, CDCl 3 ): —C (O) H (s, 9.80 ppm), PEG backbone (m, 3.20 to 4.20 ppm), —OCH 2 CH 2 C (O) H ( t, 2.60 ppm)

［実施例３］ｍＰＥＧ-アセトアルデヒドの製造 [Example 3] Production of mPEG-acetaldehyde

実施例１と同様な酸化段階を介してｍＰＥＧ（数平均分子量５Ｋ）からｍＰＥＧアセトアルデヒド（acetaldehyde）を製造し、具体的な方法は、次の通りである。   MPEG acetaldehyde is prepared from mPEG (number average molecular weight 5K) through the same oxidation step as in Example 1, and a specific method is as follows.

ｍＰＥＧ（数平均分子量５Ｋ）５０ｇをＭＣ１００ｍｌに溶解し、ＤＭＳＯ１００ｍｌを入れた後、内部温度を０〜５℃に冷却する。ピリジン（Pyridine）５ｇ、ＴＦＡ（Trifluoroacetic acid）７ｇを入れた後、同一温度で１ｈｒ撹拌する。ＤＣＣ（Dicyclohexylcarbodimide）１５ｇを入れた後、常温で２４時間反応させる。反応終了後、ろ過して析出されたＤＣＵ（Dicyclohexylurea）を除去する。ろ過後、予め用意したヘプタン／イソプロピルアルコール（Heptane／ＩＰＡ）（７：３Ｖｏｌ％）１０００ｍｌを入れて、冷却、結晶化し、収得された固体物質をＡＮ／ＭＴＢＥ（５：１）溶液を用いて再結晶した後に乾燥する。 After dissolving 50 g of mPEG (number average molecular weight 5K) in 100 ml of MC and adding 100 ml of DMSO, the internal temperature is cooled to 0 to 5 ° C. After adding 5 g of pyridine (Pyridine) and 7 g of TFA (Trifluoroacetic acid), the mixture is stirred at the same temperature for 1 hr. After putting DCC (Dicyclohexylcarbodimide) 15g, it is made to react at normal temperature for 24 hours. After completion of the reaction, DCU (Dicyclohexylurea) deposited by filtration is removed. After filtration, previously prepared heptane / isopropyl Pi alcohol (Heptane / IPA) (7: 3Vol%) Put 1000 ml, cooled, crystallized, Shutoku solid material AN / MTBE (5: 1) solution using a And recrystallized to dry.

収率：９５％（ｆｒｏｍ ｍＰＥＧ、ｂｙ ＮＭＲ ｐｕｒｉｔｙ：９９．７３％）
１Ｈ-ＮＭＲ（２００ＭＨｚ，ＣＤＣｌ３）：−Ｃ（Ｏ）Ｈ（ｓ，９．６７ｐｐｍ）、ＰＥＧ ｂａｃｋｂｏｎｅ（ｍ，３．２０〜４．２０ｐｐｍ）、−ＯＣＨ２Ｃ（Ｏ）Ｈ（ｓ，４．１８ｐｐｍ） Yield: 95% (from mPEG, by NMR purity: 99.73%)
1 H-NMR (200 MHz, CDCl 3 ): —C (O) H (s, 9.67 ppm), PEG backbone (m, 3.20 to 4.20 ppm), —OCH 2 C (O) H (s, 4.18ppm)

Claims (10)

下記式４のＰＥＧ誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させて、下記式ＡのＰＥＧアルデヒドを製造するＰＥＧアルデヒドの製造方法。


［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数である。］ A method for producing PEG aldehyde, which comprises reacting a PEG derivative of the following formula 4 with dimethyl sulfoxide and dicyclohexylcarbodiimide to produce a PEG aldehyde of the following formula A.


[Wherein, n is an integer of 3 to 2000, and k is an integer of 3 to 10. ] 前記式４のＰＥＧ誘導体にジメチルスルホキシド、トリフルオロ酢酸及びピリジンを加えて混合した後、ジシクロヘキシルカルボジイミドを入れて反応させる請求項１に記載のＰＥＧアルデヒドの製造方法。   The method for producing PEG aldehyde according to claim 1, wherein dimethyl sulfoxide, trifluoroacetic acid and pyridine are added to and mixed with the PEG derivative of formula 4 and then reacted with dicyclohexylcarbodiimide. 前記反応後、ヘプタン及びイソプロピルアルコール混合溶媒の下に結晶化した後、アセトニトリル及びメチルｔ-ブチルエーテル混合液で再結晶する過程をさらに含む請求項１に記載のＰＥＧアルデヒドの製造方法。   The method for producing PEG aldehyde according to claim 1, further comprising a step of crystallizing under a mixed solvent of heptane and isopropyl alcohol after the reaction and then recrystallizing with a mixed solution of acetonitrile and methyl t-butyl ether. 前記式４のＰＥＧ誘導体は、下記の製造段階から製造されることを特徴とする請求項１に記載のＰＥＧアルデヒドの製造方法。
ａ）下記式３のＰＥＧと下記式５のシアノアルケン（cyano alkene）を反応させて、下記式６のシアノアルキル-ＰＥＧを製造する段階；
ｂ）下記式６のシアノアルキル-ＰＥＧから式７のＰＥＧ-カルボン酸を製造する段階；
ｃ）下記式７のＰＥＧ-カルボン酸を下記式８のアルコールと反応させて、下記式９のＰＥＧ-エステル化合物を製造する段階；及び、
ｄ）下記式９のＰＥＧ-エステル化合物を還元させて、下記式４のＰＥＧ誘導体を製造する段階。







［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数、Ｒ1は（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ The method for producing PEG aldehyde according to claim 1, wherein the PEG derivative of formula 4 is produced from the following production steps.
a) reacting a PEG of formula 3 below with a cyano alkene of formula 5 below to produce a cyanoalkyl-PEG of formula 6 below;
b) preparing a PEG-carboxylic acid of formula 7 from a cyanoalkyl-PEG of formula 6 below;
c) reacting a PEG-carboxylic acid of formula 7 below with an alcohol of formula 8 below to produce a PEG-ester compound of formula 9 below; and
d) reducing a PEG-ester compound of formula 9 below to produce a PEG derivative of formula 4 below.







[Wherein, n is an integer of 3 to 2000, k is an integer of 3 to 10, and R 1 is selected from (C1 to C7) alkyl or (C6 to C20) ar (C1 to C7) alkyl groups. ] 前記ｂ）段階及びｄ）段階のうちいずれか一つ以上の段階後、反応副産物をイオン交換樹脂カラムを用いて分離する請求項４に記載のＰＥＧアルデヒドの製造方法。   The method for producing PEG aldehyde according to claim 4, wherein the reaction by-product is separated using an ion exchange resin column after one or more of the steps b) and d). 下記式１３のＰＥＧ誘導体をジメチルスルホキシド及びジシクロヘキシルカルボジイミドと反応させて、下記式ＢのＰＥＧアルデヒドを製造するＰＥＧアルデヒドの製造方法。


［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数、Ｒ2は（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ A method for producing PEG aldehyde, which comprises reacting a PEG derivative of the following formula 13 with dimethyl sulfoxide and dicyclohexylcarbodiimide to produce a PEG aldehyde of the following formula B.


[Wherein, n is an integer of 3 to 2000, k is an integer of 3 to 10, R 2 is selected from (C1 to C7) alkyl, or (C6 to C20) ar (C1 to C7) alkyl group. ] 前記式１３のＰＥＧ誘導体にジメチルスルホキシド、トリフルオロ酢酸及びピリジンを加えて混合した後、ジシクロヘキシルカルボジイミドを入れて反応させる請求項６に記載のＰＥＧアルデヒドの製造方法。   The method for producing PEG aldehyde according to claim 6, wherein dimethyl sulfoxide, trifluoroacetic acid and pyridine are added to the PEG derivative of formula 13 and mixed, and then dicyclohexylcarbodiimide is added and reacted. 前記反応後、ヘプタン及びイソプロピルアルコール混合溶媒の下に結晶化した後、アセトニトリル及びメチルｔ-ブチルエーテル混合液で再結晶する過程をさらに含む請求項６に記載のＰＥＧアルデヒドの製造方法。   The method for producing PEG aldehyde according to claim 6, further comprising a step of crystallizing under a mixed solvent of heptane and isopropyl alcohol after the reaction and then recrystallizing with a mixed solution of acetonitrile and methyl t-butyl ether. 前記式１３のＰＥＧ誘導体は、下記の製造段階から製造されることを特徴とする請求項６に記載のＰＥＧアルデヒドの製造方法。
ａ）下記式１２のアルコキシ-ＰＥＧと下記式５のシアノアルケン（cyano alkene）を反応させて、下記式１４のアルコキシ-ＰＥＧニトリル化合物を製造する段階；
ｂ）下記式１４のアルコキシ-ＰＥＧニトリル化合物から式１５のアルコキシ-ＰＥＧカルボン酸を製造する段階；
ｃ）下記式１５のアルコキシ-ＰＥＧカルボン酸を下記式８のアルコールと反応させて、下記式１６のアルコキシ-ＰＥＧエステル化合物を製造する段階；及び、
ｄ）下記式１６のアルコキシ-ＰＥＧエステル化合物を還元させて、下記式１３のＰＥＧ誘導体を製造する段階。







［式中、ｎは３〜２０００の整数、ｋは３〜１０の整数、Ｒ1及びＲ2は独立的に（Ｃ１〜Ｃ７）アルキル、または（Ｃ６〜Ｃ２０）アル（Ｃ１〜Ｃ７）アルキル基から選択される。］ The method for producing PEG aldehyde according to claim 6, wherein the PEG derivative of formula 13 is produced from the following production steps.
a) reacting an alkoxy-PEG of the following formula 12 with a cyano alkene of the following formula 5 to produce an alkoxy-PEG nitrile compound of the following formula 14;
b) preparing an alkoxy-PEG carboxylic acid of formula 15 from an alkoxy-PEG nitrile compound of formula 14 below;
c) reacting an alkoxy-PEG carboxylic acid of formula 15 below with an alcohol of formula 8 below to produce an alkoxy-PEG ester compound of formula 16 below; and
d) A step of reducing an alkoxy-PEG ester compound of the following formula 16 to produce a PEG derivative of the following formula 13.







[Wherein, n is an integer of 3 to 2000, k is an integer of 3 to 10, R 1 and R 2 are independently (C1 to C7) alkyl, or (C6 to C20) ar (C1 to C7) alkyl group. Selected from. ] 前記ｂ）段階及びｄ）段階のうちいずれか一つ以上の段階後、反応副産物をイオン交換樹脂カラムを用いて分離する請求項９に記載のＰＥＧアルデヒドの製造方法。   The method for producing PEG aldehyde according to claim 9, wherein the reaction by-product is separated using an ion exchange resin column after one or more of the steps b) and d).
JP2011510418A 2008-05-20 2009-05-19 Method for producing high-purity polyethylene glycol aldehyde derivative Active JP5371067B2 (en)

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KR1020080046802A KR100967833B1 (en) 2008-05-20 2008-05-20 A method for preparing high-purity polyethyleneglycol aldehyde derivatives
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UA98055C2 (en) 2012-04-10
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